Using mouse model systems, studies have been carried out to elucidate the mechanisms by which certain retroviruses cause leukemia and neurological disease and to identify the viral and host genes that are involved. Studies on the ME26 virus have shown that the virus transforms hematopoietic cells by a novel mechanism. The viral transforming protein was shown to transcriptionally activate an erythroid-specific transcription factor, GATA-1, and then to cooperate with GATA-1 to transactivate the erythropoietin (Epo) receptor. Studies on the Friend spleen focus-forming virus have concentrated on understanding the mechanism by which the viral envelope protein abrogates the Epo requirement of erythroid cells. The protein appears to interact with the Epo receptor, and both of these proteins have been expressed at high levels using baculovirus vectors to facilitate further studies. To understand the molecular basis for the resistance of mice to erythroleukemia induced by Friend MuLV, an endogenous, modified polytropic retrovirus has been molecularly cloned, which is expressed in Rmcf-r, but not Rmcf-s mice. Studies are in progress to determine if the expression of the env gene of this clone can block replication of polytropic viruses and inhibit F-MuLV-induced erythroleukemia. Studies on PVC-211, a variant of Friend MuLV, which causes neurological disease, but not leukemia in mice, have shown that sequences within the env gene are responsible for the pathological changes in the central nervous system, although other sequences in the 5' one-third of the viral genome are required for rapid and complete progression of disease. The failure of PVC-211 to cause erythroleukemia was shown to be due to changes in the U3 region of the LTR.